Synthesis of the C-18-C-34 fragment of amphidinolides C, C2, and C3

Article abstract of DOI:10.1021/ol400482j

The C-18-C-34 fragment of amphidinolides C, C2, and C3 and the C-18-C-29 fragment of amphidinolide F have been constructed from a trans-2,5-disubstituted dihydrofuran. This key intermediate was prepared from a dihydrofuranone formed by diastereoselective rearrangement of a free or metal-bound oxonium ylide generated from a metal carbenoid. The side chains found in amphidinolides C and F were introduced using Sonogashira coupling reactions.

Full text of DOI:10.1021/ol400482j

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1464–1467
Synthesis of the C‑18ÀC-34 Fragment
of Amphidinolides C, C2, and C3
J. Stephen Clark,* Guang Yang, and Andrew P. Osnowski
WestCHEM, School of Chemistry, Joseph Black Building, University of Glasgow,
University Avenue, Glasgow G12 8QQ, United Kingdom
stephen.clark@glasgow.ac.uk
Received February 21, 2013
ABSTRACT
The C-18ÀC-34 fragment of amphidinolides C, C2, and C3 and the C-18ÀC-29 fragment of amphidinolide F have been constructed from a trans-2,5-
disubstituted dihydrofuran. This key intermediate was prepared from a dihydrofuranone formed by diastereoselective rearrangement of a free or
metal-bound oxonium ylide generated from a metal carbenoid. The side chains found in amphidinolides C and F were introduced using
Sonogashira coupling reactions.
The amphidinolides are macrolide natural products
extracted from symbiotic dinoflagellates of the genus
Amphidinium cultivated from the Okinawan flatworms of
the Amphiscolops species. Several members of this diverse
group of macrolides exhibit potent cytotoxicity and pos-
sess other biological activities, but in most cases the
substantial quantities of material required in order to fully
establish their therapeutic potential are not available.1
Amphidinolide C2 (1) and the closely related congeners
amphidinolides C23 (2), C34 (3), and F5 (4) are particularly
attractive targets for total synthesis because of their power-
ful in vitro activities and the synthetic challenges that
their complex molecular architectures present (Figure 1).
Several groups have reported syntheses of fragments of
these natural products,2bÀd,6 but only very recently has a
total synthesis of one member of the family, amphidinolide
F (4), been published.7
Amphidinolide C was isolated by Kobayashi et al. in
1988 and was found to possess cytotoxic activity against
both murine lymphoma and epidermoid carcinoma KB
cell lines.2 Subsequently, the absolute and relative config-
urations of this and the other natural products in the series
were established and their bioactivities were determined,
(1) (a) Kobayashi, J.; Ishibashi, M. Chem. Rev. 1993, 93, 1753.
(b) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77. (c) Kobayashi,
J.; Kubota, T. J. Nat. Prod. 2007, 70, 451. (d) Kobayashi, J. J. Antibiot.
2008, 61, 271.
€
(2) (a) Kobayashi, J.; Ishibashi, M.; Walchli, M. R.; Nakamura, H.;
Hirata, Y.; Sasaki, T.; Ohizumi, Y. J. Am. Chem. Soc. 1988, 110, 490.
(b) Ishiyama, H.; Ishibashi, M.; Kobayashi, J. Chem. Pharm. Bull. 1996,
44, 1819. (c) Kubota, T.; Tsuda, M.; Kobayashi, J. Org. Lett. 2001, 3,
1363. (d) Kubota, T.; Tsuda, M.; Kobayashi, J. Tetrahedron 2003, 59,
1613.
(3) Kubota, T.; Sakuma, Y.; Tsuda, M.; Kobayashi, J. Mar. Drugs
2004, 2, 83.
(4) Kubota, T.; Suzuki, A.; Yamada, M.; Baba, S.; Kobayashi, J.
(6) (a) Shotwell, J. B.; Roush, W. R. Org. Lett. 2004, 6, 3865.
(b) Mohapatra, D. K.; Rahaman, H.; Chorghade, M. S.; Gurjar,
M. K. Synlett 2007, 4, 567. (c) Bates, R. H.; Shotwell, J. B.; Roush,
W. R. Org. Lett. 2008, 10, 4343. (d) Armstrong, A.; Pyrkotis, C.
Tetrahedron Lett. 2009, 50, 3325. (e) Mahapatra, S.; Carter, R. G.
Org. Biomol. Chem. 2009, 7, 4582. (f) Paudyal, M. P.; Rath, N. P.;
Spilling, C. D. Org. Lett. 2010, 12, 2954. (g) Ferrie, L.; Figadere, B. Org.
Lett. 2010, 12, 4976. (h) Roy, S.; Spilling, C. D. Org. Lett. 2010, 12, 5326.
(i) Morra, N. A.; Pagenkopf, B. L. Org. Lett. 2011, 13, 572.
(7) Mahapatra, S.; Carter, R. G. Angew. Chem., Int. Ed. 2012, 51,
7948.
ꢀ
ꢁ
Heterocycles 2010, 82, 333.
(5) Kobayashi, J.; Tsuda, M.; Ishibashi, M.; Shigemori, H.; Yamasu,
T.; Hirota, H.; Sasaki, T. J. Antibiot. 1991, 44, 1259.
r
10.1021/ol400482j
Published on Web 03/25/2013
2013 American Chemical Society

providing insights into the structureÀactivity relationships
synthetic plan, it is expected that dihydrofuranone vi will
serve as a precursor to the C-1 to C-7 portion of the
southern fragment i, allowing both key tetrahydrofuran-
containing fragments to be prepared from a common
intermediate.9 A similar strategy was employed by Carter
and Mahaparta in their very recent total synthesis of
amphidinolide F.7
(SARs) within this unique set of compounds.
Scheme 1. Retrosynthetic Analysis of Amphidinolide C
Figure 1. Amphidinolides C, C2, C3, and F.
The 25-membered macrolactone core of amphidinolide
C contains two 2,5-trans substituted tetrahydrofurans
embedded in its structure and an unsaturated side chain
(C-25 to C-34). The significant differences in biological
activity between amphidinolides C, C2, and F result
from structural variations in the side-chain region of
these compounds.1 The C-29 hydroxyl group confers
potent bioactivity on amphidinolide C, and the absence
of this substituent or removal of its H-bond donor
capacity by acetylation results in a 1000-fold reduction
in activity (Figure 1). This observation regarding the
SAR encouraged us to adopt a modular synthetic ap-
proach in which the side chain of amphidinolide C and
analogues would be constructed using Pd-catalyzed
coupling reactions.
The retrosynthetic analysis of amphidinolide C is shown
in Scheme 1. Initial disconnection of the lactone CÀO
bond and the C-17ÀC-18 bond leads to the ‘southern’ and
‘northern’ fragments i and ii respectively. Simplification of
the ‘northern’ fragment ii leads to the diene iii, and further
disconnection of the C-26ÀC-27 bond provides a vinylic
halide v and a propargylic alcohol iv. The latter can be
obtainedfrom atrans2,5-disubstituted dihydrofuranonevi
of a type generated by a highly diastereoselective metal-
mediated reaction of the diazo ketone vii.8 In the overall
The requisite dihydrofuranone was prepared from di-
methyl D-malate (Scheme 2). Selective reduction of the
R-hydroxy ester using the procedure by Saito et al. pro-
vided a diol,10 the primary hydroxyl group of which was
protected to give the TBS ether 6. The remaining secondary
hydroxyl group was then allylated using the acid-catalyzed
reaction of an imidate to afford the allyl ether 7.11
Saponification of the ester provided the carboxylic acid
8, and activation of this as a mixed anhydride followed by
treatment with a solution of diazomethane gave the
R-diazo ketone 9. Treatment of this compound with
Cu(acac)2 in THF at reflux afforded the dihydrofuranone
10 as a single isomer in high yield.8
Following the synthesis of the ketone 10, the first
challenge was the deletion of the carbonyl group from
the ring to provide the tetrahydrofuran corresponding to
the C-18 to C-24 subunit of amphidinolide C. Initial
attempts to perform removal of the ketone were under-
taken by formation of a tosyl hydrazone followed by
(9) Clark, J. S.; Yang, G.; Osnowski, A. P. Org. Lett. 2013, 15, DOI:
10.1021/ol4004838.
(10) (a) Saito, S.; Hasegawa, M.; Inaba, M.; Nishida, R.; Fujii, T.;
Nomizu, S.; Moriwake, T. Chem. Lett. 1984, 1389. (b) Saito, S.;
Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T. Tetrahedron 1992,
48, 4067.
(8) (a) Pirrung, M. C.; Werner, J. A. J. Am. Chem. Soc. 1986, 108,
6060. (b) Roskamp, E. J.; Johnson, C. R. J. Am. Chem. Soc. 1986, 108,
6062. (c) Clark, J. S. Tetrahedron Lett. 1992, 33, 6193. (d) Clark, J. S.;
Krowiak, S. A.; Street, L. J. Tetrahedron Lett. 1993, 34, 4385. (e) Clark,
J. S.; Whitlock, G. A. Tetrahedron Lett. 1994, 35, 6381. (f) Clark, J. S.;
Whitlock, G.; Jiang, S.; Onyia, N. Chem. Commun. 2003, 2578. (g) Clark,
J. S.; Fessard, T. C.; Wilson, C. Org. Lett. 2004, 6, 1773. (h) Clark, J. S.;
Fessard, T. C.; Whitlock, G. A. Tetrahedron 2006, 62, 73.
(11) (a) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J. Chem. Soc.,
€
Perkin Trans. 1 1985, 2247. (b) Kruger, J.; Hoffmann, R. W. J. Am.
Chem. Soc. 1997, 119, 7499.
Org. Lett., Vol. 15, No. 7, 2013
1465

Scheme 2. Synthesis of trans-Dihydrofuranone 10
Scheme 3. Synthesis of Propargylic Alcohol 16
reduction.12 However, this approach was unsuccessful and
so the use of radical deoxgenation methods was explored
(Scheme 3). The ketone 10 was reduced to a diastereomeric
mixture of alcohols 11 that were then converted into the
corresponding xanthate esters. Treatment of this mixture
under BartonÀMcCombie conditions delivered the deox-
ygenated tetrahydrofuran 12.13 Ozonolysis and reduction
thenafforded the alcohol 13 in an overall yield of 73% over
four steps, with minimal purification necessary. Protection
of the primary alcohol as a tert-butyldiphenylsilyl ether
followed by selective acid-catalyzed removal of the TBS
group generated the alcohol 14. Oxidation of the primary
alcohol using the Dess-Martin protocol provided the
aldehyde 15 required for the addition of an alkyne
nucleophile.
Several sets of reaction conditions were examined in an
effort to perform a stereoselective nucleophilic attack on
the aldehyde 15. Attempted reagent-controlled introduc-
tion of the alkyne using Carriera’s alkynylation protocol14
did not proceed efficiently. Efforts to achieve substrate
control by using various alkyne nucleophiles and reaction
conditions were not successful; a 1.5:1 mixture of the
diastereomeric propargylic alcohols 16a and 16b was
obtained from the reaction performed with magnesium
trimethylsilylacetylide in THF at À78 °C. Oxidation of the
mixture of alcohols to the corresponding ynone proceeded
in good yield, but attempted stereoselective ketone reduc-
tionusingL-selectride or under Lucheconditions atÀ78°C
resulted in little stereocontrol (1:1 and 1.5:1 of 16a:16b,
respectively) .
methylenated under Mannich conditions,15 and the result-
ing enal was subjected to the Grignard addition of TMS
acetylene to provide a racemic mixture of propargylic
alcohols 17. Kinetic resolution was then performed using
Sharpless asymmetric epoxidation, and the allylic alcohol
(S)-17 was obtained with 98% ee.16 TBS protection of the
secondary alcohol, removal of the TMS group, and sub-
jection of the resulting terminal alkyne to modified Negishi
carboalumination and iodination conditions17 provided
the unstable E-vinylic iodide 19 stereoselectively and in
good yield.
Although it was possible to separate the diastereomeric
alcohols 16a,b, the mixture was used in the subsequent
step. Coupling of the vinylic iodide 19 to a mixture of the
propargylic alcohols 16a,b under Sonogashira conditions
was achieved in 82% yield (Scheme 5).18 The propargylic
alcohol functionality of the coupled products 20a,b al-
lowed stereoselective reduction of the alkyne to be
achieved using Red-Al to give the desired E-configured
alkenes 21a,b.6i Oxidation of the diastereomeric mixture of
allylic alcohols to give the enone was accomplished in
quantitative yield using the Dess-Martin periodinane. A
subsequent stereoselective Luche reduction of the dienone
provided the alcohol 21a corresponding to the entire C-18
Following preparation of the propargylic alcohols
16a,b, attention turned to the synthesis of the vinylic
iodide coupling partner 19 (Scheme 4). Hexanal was
(15) Ragoussis, V.; Giannikopoulos, A.; Skoka, E.; Grivas, P.
J. Agric. Food Chem. 2007, 55, 5050.
(16) Martin, V. S.; Woodward, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,
M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237.
(17) Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1068.
(12) (a) Caglioti, L. Tetrahedron 1966, 22, 487. (b) Hutchins, R. O.;
Milewski, C. A.; Maryanoff, B. E. J. Am. Chem. Soc. 1973, 95, 3662.
(13) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
(14) (a) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687. (b) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4,
2605.
ꢀ
(18) (a) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874. (b)
ꢀ
Chinchilla, R.; Najera, C. Chem. Soc. Rev. 2011, 40, 5084.
1466
Org. Lett., Vol. 15, No. 7, 2013

The power of the Sonogashira coupling reaction for the
installationofa range oftailunitswasfurther illustrated by
the construction of the C-18ÀC-29 fragment of amphidi-
nolide F (Scheme 6). In this case, a copper-free variant of
the Sonogashira reaction19 was used to couple 1-bromo-2-
methylpropene to the alkyne 16a.20 This modification to
the procedure was required because significant homocou-
pling of the alkyne was encountered when the reaction
was performed in the presence of copper iodide. When
pyrrolidine was used as the solvent, clean coupling oc-
curred to provide 22 in 75% yield. The propargylic alcohol
was reduced to the corresponding E-allyl alcohol 23 in an
analogous manner to the reduction of 20a,b (Scheme 5).
Scheme 4. Stereoselective Synthesis of Vinylic Iodide 19
Scheme 6. Completion of the C-18ÀC-29 Fragment of
Amphidinolide F
Scheme 5. Completion of the C-18ÀC-34 Fragment
of Amphidinolide C
In summary, we have synthesized the C-18ÀC-34 frag-
ment of amphidinolide C and the C-18ÀC-29 fragment of
amphidinolide F using routes in which diastereoselective
rearrangement of the diazo ketone 9 is used to construct
the key trans-2,5-disubstituted tetrahydrofuran. The entire
‘northern’ fragments 21a and 23 were constructed from
16 using Sonogashira coupling reactions to install
the side chains found in the natural products. Stereo-
selective enone reduction was used to control the stereo-
chemistry at C-24 in the case of the C-18ÀC-34 fragment
of amphidinolide C.
Acknowledgment. The authors acknowledge WestCH-
EM, CSC, EPSRC, and the University of Glasgow for
funding.
to C-34 fragment in 83% yield as a single stereoisomer
through FelkinÀAnh control.
(19) Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993,
34, 6403.
Supporting Information Available. Experimental pro-
cedures and data for 7À23. This material is available free
of charge via the Internet at http://pubs.acs.org.
(20) Alcohol 16a could be obtained as a single diastereomer by addition
of lithium trimethylsilylacetylide to the aldehyde 15, treatment of resulting
diastereomeric alcohols with dicobalt octacarbonyl, chromatographic sep-
aration of the diastereomeric cobalt complexes, and oxidative removal of
cobalt followed by desilylation (see Supporting Information for full details).
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
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